Melanin-concentrating hormone (MCH) is primarily expressed in the hypothalamus and plays a significant role in feeding behavior and energy balance. Although there are reports in the literature describing the presence of MCH in the gastrointestinal tract as well as on immune cells, peripheral roles for MCH have not yet been established. We discovered that MCH and its receptor MCHR1 were several fold upregulated in the intestinal mucosa of patients with Inflammatory Bowel Disease (IBD), and most importantly, that expression of MCHR1 was significantly higher in patients with more advanced disease. Laser capture microdissection followed by real time RT-PCR analysis demonstrated that colonocytes from IBD biopsies had increased expression of MCHR1 mRNA, compared to colonocytes obtained from controls. These findings made us hypothesize a proinflammatory role of MCH in the pathophysiology of IBD. This hypothesis is supported by our preliminary data describing that TNBS-induced experimental colitis is significantly attenuated in the MCH deficient mice. In the same model of intestinal inflammation, MCH immunoneutralization resulted in similar protective effects. Moreover, we found that activation of MCH receptors in colonocytes triggers proinflammatory signaling pathways and cytokine production. In the current proposal, we will pursue three specific aims: In aim 1, we will investigate the effects of MCH genetic deficiency and MCHR1 peripheral antagonism in three different models of acute and chronic experimental colitis. In aim 2, we will examine the role of MCH in intestinal neuroimmune and epithelial-immune cell interactions. In aim 3 we will delineate the downstream effectors of MCH signaling in human colonic epithelial cells. Our proposal will be the first to decipher the mechanistic links between MCH and intestinal inflammation and may provide the foundation for the development of novel, MCH-based treatments for IBD and perhaps for additional inflammatory conditions of the gastrointestinal system and beyond. PUBLIC HEALTH RELEVANCE: Melanin-Concentrating Hormone (MCH) is a neuropeptide that is produced in the brain and physiologically regulates food intake and body weight, thus it serves as an important target to treat obesity. Our preliminary studies have revealed a previously unrecognized role for MCH in intestinal inflammation, including Inflammatory Bowel Disease (IBD), which currently affects one million of Americans. Experiments outlined in this proposal will uncover the mechanisms by which MCH mediates intestinal inflammation and test an MCH antagonist as a novel approach to treat IBD and perhaps additional inflammatory conditions.